SK152097A3 - 3-amido-chromanylsulfonyl (thio)ureas, process for their preparation, their use and medicaments containing them - Google Patents

Abstract

Disclosed are 3-amido-chromanylsulphonyl(thio)ureas of general formula (I), wherein R1 = H, C1-4-alkyl, C1-4-alkoxy, C1-4-alkoxy-C1-4-alkoxyl, C1-4-alkylthio group, F, Cl, Br, I or CF3; R2a, R2b and R2c = H, or C1-2-alkyl; R3 = H or C1-4-alkyl; Z = O or S; A = phenyl (optionally substituted), saturated or unsaturated lactam residue or heterocyclic bicyclic system residua and physiologically acceptable salts thereof, which are important active substances for medicaments for treatment of cardial and circulatory systems defect, particularly for treatment of arrhythmias, to prevent sudden heart death or to effect the lower contractility of heart, as well as the processes for preparation of these compounds, their use and pharmaceutical substances containing them.

Description

The invention relates to 3-amidochromanylsulfonyl (thio) ureas of the formula I

in which the individual general symbols have the meanings given below, and which are valuable active substances for medicaments for the treatment of cardiac and circulatory system disorders, in particular for the treatment of arrhythmias, the prevention of sudden cardiac death or influencing the reduced contractility of the heart uses and pharmaceutical preparations containing them.

BACKGROUND OF THE INVENTION Certain benzenesulfonylureas are known to cause a reduction in the amount of blood sugar. Glibenclamide serves as a prototype of such a sulphonylurea, reducing the amount of blood sugar, which is used therapeutically as a treatment for diabetes mellitus, and serves as a very important tool in the investigation of so-called ATP-sensitive potassium channels. In addition to its action to reduce blood sugar, glibenclamide has other effects that hitherto cannot be used therapeutically but which together lead to blocking of these ATP-sensitive potassium channels. This includes, in particular, antifibrilatory action on the heart. However, concomitant reduction of blood sugar would be undesirable or even dangerous in the treatment of ventricular fibrillation or its precursors, as this could further aggravate the patient's condition. EP-A-612 724 discloses benzenesulfonylureas which act on the heart and circulatory systems. German patent application 19546736.1 or EP-A-779 288 discloses chromanylsulfonyl (thio) -ureas acting on the cardiac and circulatory systems in which an amido group is attached to the chromane system at the 4-position via a methylene or ethylene group. However, the properties of these compounds are not yet satisfactory from various points of view, and there remains a need to find compounds with favorable properties, particularly useful in the treatment of arrhythmical heart disorders and their consequences.

EP-A-325 964 discloses chromate derivatives as < 2-adrenergic antagonists with effects against depression, metabolic disorders, glaucoma, migraine and high blood pressure. However, this document does not disclose any compounds which are substituted by a sulphonylurea or a sulphonylthiourea moiety and these compounds are also not evident therefrom.

SUMMARY OF THE INVENTION

It has now surprisingly been found that the chromanylsulfonyl (thio) ureas of the general formula I having an amido group in the 3-position of the chromate system show a marked action on the cardiac and circulatory systems. The invention therefore provides compounds of formula I

In which

R1 represents a hydrogen atom, an alkyl group having 1, 2, 3 or 4 carbon atoms, an alkoxy group having 1, 2, 3 or 4 carbon atoms, an alkoxyalkoxy group containing, independently of each alkoxy unit, 1, 2, 3 or 4 carbon atoms, an alkylthio group having 1 , 2, 3 or 4 carbon atoms, fluorine, chlorine, bromine or iodine or trifluoromethyl, R2a _of R2b _and r2c _, which are the same or different, each represent a hydrogen atom or an alkyl group having 1 or 2 carbon atoms, r3 represents a hydrogen atom or an alkyl group having 1, 2, 3 or 4 carbon atoms

Z represents a sulfur or oxygen atom, and

A represents a phenyl group which is unsubstituted or substituted by up to three identical or different substituents selected from the group consisting of halogen atoms, alkyl groups having 1 or 2 carbon atoms and alkoxy groups having 1 or 2 carbon atoms, or A represents the remainder of a saturated or unsaturated lactam of formula ___

ABOUT

where

B represents an alkenylene or alkylene group having 3, 4, 5 or 6 carbon atoms which is unsubstituted or substituted by up to three identical or different alkyl groups having 1, 2, 3 or 4 carbon atoms, or A represents the rest of the bicyclic system of one of the formulas

O in all their stereoisomeric forms and mixtures thereof in all ratios, as well as their physiologically acceptable salts.

The term alkyl refers to saturated hydrocarbon radicals and straight or branched chain, unless stated otherwise. This also applies to alkyl radicals which are contained in alkoxy groups, i.e. alkyl-Ο-, alkoxyalkoxy radicals, i.e. alkyl-O-alkyl-O-, or alkylthio groups, i.e. alkyl-S- radicals. Examples of alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl and tert-butyl. Examples of alkoxy include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy and tert-butoxy. Examples of alkoxyalkoxy include methoxymethoxy, ethoxymethoxy, n-butoxymethoxy, 2-methoxyethoxy, 2-ethoxyethoxy, 2-isopropoxyethoxy, 2- (n-propoxy) ethoxy, 2- (n-butoxy) ethoxy, 2 (n-butoxy) ethoxy, 2 ethoxy, 3-methoxypropoxy, 3-ethoxypropoxy, 4-methoxybutoxy, 4-ethoxybutoxy and 3-methoxybutoxy.

Examples of alkylene and alkenylene groups in Group B include 1,3-propylene, 1,4-butylene, 1,5-pentylene, 1,6-hexylene, 1,3-prop-1-enylene, 1,3-prop -2-enylene, 1,4-but-1-enylene, 1,4-but-2-enylene, 1,4-but-3-enylene, 1,5-pent-1-enylene, 1,5-pent -2-enylene, 1,5-pent-3-enylene and 1,5-pent-4-enylene.

In substituted phenyl radicals, which may be substituted in particular one, two or three times, the substituents may be in any position, for example in monosubstitution in the ortho, meta or para position, in the disubstitution in the 2,3-, 2,4-position -, 2,5-, 2,6-, 3,4- or 3,5- and in the trisubstitution, for example in the 2,3,4-, 2,3,5-, 2,3,6-, 2-positions, 4,5-, 2,4,6- or 3,4,5-.

The term halogen means, unless otherwise indicated, fluorine, chlorine, bromine and iodine, preferably fluorine and chlorine.

The compounds of formula I may contain one or more centers of chirality, for example at the carbon atoms of the 2 or 3 chromate system with the appropriate substitution, and may exist in stereoisomeric forms. The chiral centers present may be independently in the R- or S-configuration. The present invention includes all possible stereoisomers, for example enantiomers or diastereomers, and mixtures of two or more stereoisomers in any ratios. The invention relates to enantiomers, for example in the form of pure enantiomers as well as in the form of left-handed or dextrorotatory antipodes, in the form of racemates and in the form of mixtures of the two enantiomers in arbitrary proportions.

The compounds of the formula I according to the invention contain mobile hydrogen atoms and can exist in various tautomeric forms. The present invention also relates to all of these tautomers.

In particular, the physiologically acceptable salts of the compounds of formula I are pharmaceutically usable salts or non-toxic salts. Such salts can be prepared, for example, from compounds of the formula I with acidic hydrogen atoms and non-toxic inorganic or organic bases, for example suitable alkali metal or alkaline earth metal compounds such as sodium or potassium hydroxide, ammonia or organic amino compounds or ammonium hydroxide. The reactions of the compounds of formula I with bases to form salts are generally carried out by conventional procedures in a solvent or diluent. Preferred are physiologically acceptable salts of the compounds of formula I in which alkali and alkaline earth metal ions, such as sodium, potassium, rubidium, magnesium and calcium ions, unsubstituted ammonium ion or ammonium ions with one or more organic residues such as and addition products of compounds of formula I and amino acids, in particular basic amino acids such as lysine or arginine. Formation of a salt on a nitrogen atom in the urea moiety which is substituted with a sulfonyl group yields compounds of formula II

in which R1, R2a, R2b _of R2c, R3 _of A and Z are as defined above and the cation M 'is, for example, an alkali metal ion or one equivalent of an alkaline earth metal ion, for example sodium, potassium, rubidium, magnesium or calcium ion unsubstituted an ammonium ion or an ammonium ion containing one or more organic residues, for example a cation obtained from an amino acid, in particular a basic amino acid, such as lysine or arginine, by protonation.

R1 preferably represents a hydrogen atom, an alkyl group having 1 or 2 carbon atoms, an alkoxy group having 1, 2, 3 or 4 carbon atoms, an alkylthio group having 1, 2, 3 or 4 carbon atoms, a fluorine, chlorine, bromine or iodine atom or trifluoromethyl especially hydrogen, C1-C2 alkyl, C1-C2 alkoxy, C1-C2 alkylthio, fluoro, chloro, bromo or iodo or trifluoromethyl, and particularly preferably hydrogen, an alkyl group having 1 or 2 carbon atoms, an alkoxy group having 1 or 2 carbon atoms or an alkylthio group having 1 or 2 carbon atoms.

Preferably R 2a is a hydrogen atom. R2b and R2c preferably each independently represent a hydrogen atom or a methyl group, particularly preferably a hydrogen atom.

Preferably R3 is hydrogen, methyl or ethyl.

Preferred are compounds of formula I wherein R1 is hydrogen, alkyl having 1 or 2 carbon atoms, alkoxy having 1, 2, 3 or 4 carbon atoms, alkylthio having 1, 2, 3 or 4 carbon atoms, fluorine, chlorine, bromine or iodine or trifluoromethyl, R2a _of R2b _and R2c _, which are the same or different, in each case preferably hydrogen or alkyl of 1 or 2 carbon atoms, r3 represents a hydrogen atom or an alkyl group of 1, 2, 3 or 4 carbon atoms

Z represents a sulfur or oxygen atom, and

A represents a phenyl group which is unsubstituted or substituted by up to three identical or different substituents selected from the group consisting of halogen atoms, alkyl groups having 1 or 2 carbon atoms and alkoxy groups having 1 or 2 carbon atoms, or A represents the remainder of a saturated or unsaturated lactam of formula

ABOUT

where

B represents an alkenylene or alkylene group having 3, 4, 5 or 6 carbon atoms which is unsubstituted or substituted by up to three identical or different alkyl groups having 1, 2, 3 or 4 carbon atoms, or A represents the rest of the bicyclic system of one of the formulas

ABOUT

Particular preference is given to compounds of the formula I in which R1 represents a hydrogen atom, an alkyl group having 1 or 2 carbon atoms, an alkoxy group having 1 or 2 carbon atoms, an alkylthio group having 1 or 2 carbon atoms, a fluorine, chlorine, bromine or iodine atom or trifluoromethyl. group

R 2a represents a hydrogen atom R 2b _and r 2c each represent a hydrogen atom or a methyl group, r 3 represents a hydrogen atom or an alkyl group having 1, 2, 3 or 4 carbon atoms

Z represents a sulfur or oxygen atom, and

A represents a phenyl group which is unsubstituted or substituted by up to three identical or different substituents selected from the group consisting of halogen atoms, alkyl groups having 1 or 2 carbon atoms and alkoxy groups having 1 or 2 carbon atoms, or A represents the remainder of a saturated or unsaturated lactam of formula

Ek / N where

B represents an alkenylene or alkylene group having 3, 4, 5 or 6 carbon atoms which is unsubstituted or substituted by up to three identical or different alkyl groups having 1, 2, 3 or 4 carbon atoms, or A represents the rest of the bicyclic system of one of the formulas

ABOUT

ABOUT

ABOUT

One group of particularly preferred compounds are those compounds of formula (I) wherein:

R1 represents a hydrogen atom, an alkyl group having 1 or 2 carbon atoms, an alkoxy group having 1 or 2 carbon atoms, an alkylthio group having 1 or 2 carbon atoms, R2a, R2b _and r2c each represent a hydrogen atom, r3 represents a hydrogen atom or an alkyl group with 1 , 2, 3 or 4 carbon atoms

Z represents a sulfur atom, and

A represents a phenyl group which is unsubstituted or substituted by up to three identical or different substituents selected from the group consisting of halogen atoms, alkyl groups having 1 or 2 carbon atoms and alkoxy groups having 1 or 2 carbon atoms, or A represents the remainder of a saturated or unsaturated lactam of formula

where

B represents an alkenylene or alkylene group having 3, 4, 5 or 6 carbon atoms which is unsubstituted or substituted by up to three identical or different alkyl groups having 1, 2, 3 or 4 carbon atoms, or A represents the rest of the bicyclic system of one of the formulas

In this group, even more preferred are compounds of formula (I) wherein R 1 is a compound of formula I; is H, alkyl having 1 or 2 carbon atoms, alkoxy having 1 or 2 carbon atoms or alkylmercapto having 1 or 2 carbon atoms, the symbols R 2 _of RZB _and R 2c are hydrogen, R 3 is hydrogen, methyl or ethyl, Z is a sulfur atom, and

A represents a phenyl group which is unsubstituted or substituted by up to three identical or different substituents selected from the group consisting of halogen atoms, alkyl groups having 1 or 2 carbon atoms and alkoxy groups having 1 or 2 carbon atoms, or A represents the remainder of a saturated or unsaturated lactam of formula

About where

B represents an alkenylene or alkylene group having 3, 4, 5 or 6 carbon atoms which is unsubstituted or substituted by up to three identical or different alkyl groups having 1, 2, 3 or 4 carbon atoms,

Particularly preferred in this group are compounds of formula I in which

R1 represents a hydrogen atom, an alkyl group having 1 or 2 carbon atoms, an alkoxy group having 1 or 2 carbon atoms or an alkylthio group having 1 or 2 carbon atoms, R2a, p2b _and r2c each represent a hydrogen atom,

R 3 is hydrogen, methyl or ethyl Z is sulfur, and

A represents a phenyl group which is unsubstituted or substituted by up to three identical or different substituents selected from the group consisting of halogen atoms, alkyl groups having 1 or 2 carbon atoms and alkoxy groups having 1 or 2 carbon atoms.

Another group of particularly preferred compounds are those compounds of formula (I) wherein:

R1 represents a hydrogen atom, an alkyl group having 1 or 2 carbon atoms, an alkoxy group having 1 or 2 carbon atoms or an alkylthio group having 1 or 2 carbon atoms, R2a, R2b _and r2c each represent a hydrogen atom, r3 represents a hydrogen atom or an alkyl group with 1 , 2, 3 or 4 carbon atoms,

Z represents an oxygen atom, and

A represents a phenyl group which is unsubstituted or substituted by up to three identical or different substituents selected from the group consisting of halogen atoms, alkyl groups having 1 or 2 carbon atoms and alkoxy groups having 1 or 2 carbon atoms.

or A represents a residue of a saturated or unsaturated lactam of the general formula:

ABOUT

where

B represents an alkenylene or alkylene group having 3, 4, 5 or 6 carbon atoms which is unsubstituted or substituted by up to three identical or different alkyl groups having 1, 2, 3 or 4 carbon atoms, or A represents the rest of the bicyclic system of one of the formulas

ABOUT

ABOUT

In this further group, even more preferred are compounds of formula I in which

R1 represents a hydrogen atom, an alkyl group having 1 or 2 carbon atoms, an alkoxy group having 1 or 2 carbon atoms or an alkylthio group having 1 or 2 carbon atoms, R2a, R2b _and r2c each represent a hydrogen atom,

R 3 represents a hydrogen atom, a methyl or ethyl group

Z represents an oxygen atom, and

A represents a phenyl group which is unsubstituted or substituted by up to three identical or different substituents selected from the group consisting of halogen atoms, alkyl groups having 1 or 2 carbon atoms and alkoxy groups having 1 or 2 carbon atoms.

In this further group, compounds of the formula I in which

R1 represents a hydrogen atom, an alkyl group having 1 or 2 carbon atoms, an alkoxy group having 1 or 2 carbon atoms or an alkylthio group having 1 or 2 carbon atoms, R2a, R2b _and r2c each represent a hydrogen atom,

R 3 represents a hydrogen atom, a methyl or ethyl group Z represents an oxygen atom, and

A represents a phenyl group which is unsubstituted or substituted by up to three identical or different substituents selected from the group consisting of halogen atoms, alkyl groups having 1 or 2 carbon atoms and alkoxy groups having 1 or 2 carbon atoms.

For all preferred compounds of formula I, all stereoisomeric forms thereof and mixtures thereof in all proportions, as well as their physiologically acceptable salts, are also an object of the invention.

The invention further relates to a process for the preparation of compounds of formula I which comprises the following reaction steps: j (a) 3-Amidochromanylsulfonyl (thio) ureas of formula I in which r 3 is other than hydrogen may be prepared by chromanylsulfonamides or a compound of formula III

Η

R 'is a salt of formula IV

Ο

2b (III)

(IV) are reacted with R 3 -substituted isocyanates of formula V or with R 3 -substituted isothiocyanates of formula VI

R-N = C = O (V) R-N = C = S (VI) to form substituted chromanylsulfonylureas of formula Ia

optionally substituted chromanylsulfonylthioureas of formula 1b

R (lb)

The radicals R1, r2h _of R2b _of r2c and A in the formulas Ia, Ib, III and IV have the meanings given above and r3 represents in the formulas Ia and Ib and in the formulas V and VI an alkyl group having 1, 2, 3 or 4 carbon atoms. Suitable cations M in the salts of the formula IV are, for example, alkali metal or alkaline earth metal ions, for example sodium or potassium ion, or suitable ammonium ions which do not react undesirably with the reactants, in particular tetraalkylammonium ions or trialkylbenzylammonium ions.

Equivalents to the R 3 -substituted isocyanates of formula V can be R 1 -substituted carbamic acid esters, R 3 -substituted carbamic acid halides, or R 3 -substituted ureas.

(b) The chromanylsulfonylureas of the formula Ia can be prepared from the chromanylsulfonamides of the formula III or their salts of the formula IV by reaction with R3-substituted trichloroacetamides of the formula VII

Cl \ H 3 CIV _N -R (VII) Cl (1 0 wherein r 3 is alkyl group with 1, 2, 3 or 4 atoms carbon, in the presence of a base in an inert solvent such as described in Synthesis 1987, 734 - 735, at temperatures ¹ 25 to 150 ° C.

Suitable bases are, for example, alkali or alkaline earth metal hydroxides, hydrides, amides or alkoxides, such as sodium hydroxide, potassium hydroxide, calcium hydride, sodium amide, potassium amide, sodium methoxide, potassium methoxide or potassium ethoxide. Suitable inert solvents are ethers such as tetrahydrofuran (THF), dioxane, ethylene glycol dimethyl ether or diglyme, ketones such as acetone or butanone, nitriles such as acetonitrile, nitro compounds such as nitromethane, esters such as ethyl acetate, amides such as dimethylformamide (DMF), N-methyl15 pyrrolidone (NMP) or hexamethylphosphoric triamide (hexamethylphosphoric triamide), sulfoxides such as dimethyl sulfoxide (DMSO), sulfones such as sulfolane, or hydrocarbons such as benzene, toluene or xylene. Mixtures of these solvents with one another are also suitable.

(c) Chromanylsulfonyl (thio) ureas of formula I in which r 3 is hydrogen may be prepared by reacting the chromanylsulfonamides of formula III or salts thereof of formula IV with trialkylsilylizo (thio) cyanates, for example trimethylsilylizo (thio) ) cyanate, or with silicon tetrachloro (thio) cyanate and primarily silicon-substituted chromanylsulfonyl (thio) ureas are cleaved. When trialkylsilyl isocyanates or silicon tetraisocyanates are used, compounds of formula Ic are obtained

and when trialkylsilyl isothiocyanates or silicon tetra-isothiocyanates are used, compounds of formula Id are obtained

wherein R1, R2a _of R2b, r2c and A in formulas Ic and Id have the meanings given above.

Further, the chromanylsulfonamides of the formula III or their salts of the formula IV can be converted to the chromanylsulfonylureas Ic by reaction with halocyanates and hydrolysis of the primary N-cyanosulfonamides formed with mineral acids at temperatures of 0 to 100 ° C.

The chromanylsulfonylthioureas of formula Id can also be obtained by reacting the chromanylsulfonylamides of formula III or salts thereof of formula IV with benzoylisothiocyanate and reacting the intermediate benzoyl substituted chromanylsulfonylthioureas with an aqueous mineral acid solution, as described in J. Med. Chem. 35, 1137-1144 (1992). A further variant of the preparation of the compounds of the general formula (Id) consists in reacting the above-mentioned N-cyanosulfonamides with sulfane.

(d) The chromanylsulfonylureas of the formula I in which Z represents an oxygen atom can be prepared, for example, from the chromanylsulfonyl halides of the formula VIII

wherein the symbols R, R 2 and _the R 2b R 2c _{of the} A as defined above, by reaction with R 3 -substituted ureas or R 3 -substituted bis (trilalkylsilyl) ureas. Further, the sulfonic acid chlorides of formula VIII can be reacted with parabanoic acid to form chromanylsulfonylparabanic acids. Their hydrolysis with mineral acids yields the corresponding chromanylsulfonylureas of the formula I in which Z represents an oxygen atom.

(e) Chromanylsulfonyl (thio) ureas of formula (I) may also be prepared by reacting amines of formula R3-NH2 in which r3 is as defined above with chromanylsulfonylisocyanates of formula (IX)

optionally with chromanylsulfonyl isothiocyanates of formula X

wherein R1, R2a, R2b, r2c and A in formulas IX and X have the meanings given above. To obtain a compound of formula I, an amine of formula R3-NH2, as well as iso (thio) cyanates of formula IX or X, can also be reacted with a chromanylsulfonylcarbamic ester, chromanylsulfonylcarbamide halide or chromanylsulfonylurea of formula Ia where r3 is hydrogen. The amine of formula R3-NH2 may also be reacted with a chromanylsulfonylcarbamic acid thioester or a chromanylsulfonylcarbamic acid thiohalide to give a compound of formula I wherein Z is sulfur.

Sulfonylisocyanates of general formula. of formula IX can be obtained from the sulfamoylchromans of formula III by conventional procedures, for example using phosgene. The sulfonylisothiocyanates of formula X can be prepared by reacting the corresponding sulfonic acid amide of formula III with an alkali metal hydroxide and carbon disulfide in an organic solvent such as dimethylformamide, dimethylsulfoxide or N-methylpyrrolidine. The two alkali metal sulfonyldithiocarbamic acid salt thus obtained may be reacted with a slight excess of phosgene or a phosgene replacer such as triphosgene, with two equivalents of chloroformic acid ester or with thionyl chloride in an inert solvent. The sulfonyl isothiocyanate solution thus obtained can be directly reacted with the corresponding amines or ammonia.

(f) Substituted chromanylsulfonylureas of formula I wherein Z is O may be prepared by conversion from chromanylsulfonylthioureas of formula I wherein Z is sulfur. Desulfurization, i.e. replacement of the sulfur atom in the correspondingly substituted chromanylsulfonylthiourea with an oxygen atom, can be carried out, for example, with oxides or salts of heavy metals, as well as using oxidizing agents such as hydrogen peroxide, sodium peroxide or nitrous acid. The thiourea may also be desulfurized by reaction with a chlorinating agent such as phosgene or phosphorus pentachloride. As intermediates, amidines of chloroformic acid or carbodiimides are obtained, which can be converted, for example, by saponification or addition of water, to the correspondingly substituted chromanylsulfonylureas.

(g) Correspondingly substituted chromanylsulphenylureas or chromanylsulphinylureas can be oxidized to a chromanylsulphonylureas of the formula I in which Z represents an oxygen atom with an oxidizing agent such as hydrogen peroxide, sodium peroxide or nitrous acid.

The starting compounds for the above syntheses of chromanylsulfonyl (thio) ureas of formula (I) may be prepared by methods already known in the literature (for example, in standard works such as Houben-Weyl, Methoden der Organischen Chemie, Georg Thieme Verlag, Stuttgart; Organic Reactions, John Willey and Sons, Inc., New York, as well as in the above-mentioned patent applications, using reaction conditions that are known and appropriate for the above reactions, but known variants of these reactions, but not described, may also be used. if desired, formed in situ, in such a way that they are not isolated from the reaction mixture but are immediately reacted.

The 3-amidochromans of formula (XVI) can be prepared, for example, by the method outlined in Scheme I, in which the individual substituents have the meanings given above, or as explained below,

Scheme I

(xi) / (X)

(Xii) (xiv)

(XVI) (XV) means a phenyl group which is unsubstituted or substituted by up to three identical or different substituents selected from the group consisting of halogen atoms, alkyl groups having 1 or 2 carbon atoms and alkoxy groups having 1 or 2 carbon atoms, or alkyl groups having 1 up to 4 carbon atoms or trihalomethyl.

The oximes of formula XI, as described, for example, in Heterocycles 38, 305-318 (1994), can be reacted with sulfonic acid chlorides, for example p-toluenesulfonic acid chloride, by addition of a tertiary base such as pyridine or trialkylamine, in the presence or in in the absence of an inert solvent, at temperatures of from 0 to 100 ° C, in particular at temperatures of from 0 to 10 ° C, to give oxime sulfonates, for example oxime tosylates of formula XII. Suitable inert solvents are, for example, ethers such as tetrahydrofuran, dioxane or glycol ether, ketones such as acetone or butanone, nitriles such as acetonitrile, amides such as dimethylformamide, N-methylpyrrolidone or hexamethylphosphoric triamide, sulfoxides such as dimethyl sulfoxide, chlorinated carbon is dichloromethane, chloroform, trichlorethylene, 1,2-dichloroethane or carbon tetrachloride, or hydrocarbons such as benzene, toluene or xylene. Mixtures of these solvents with one another are also suitable.

The oxime sulfonates of formula (XII) can be converted into aminoketones, i.e. 3-amino-4-chromanones, by treatment with bases in a solvent. These compounds are generally isolated in the form of acid addition salts, for example, the hydrochloride of formula XIII (J. Med. Chem. 12, 277 (1969)). Suitable bases for this reaction are, for example, alkali metal salts of alcohols such as sodium methoxide, sodium ethoxide, sodium isopropoxide, potassium methoxide, potassium ethoxide or potassium tert-butoxide, but also tertiary amine bases such as pyridine or trialkylamines. Suitable solvents are, for example, alcohols, such as methanol, ethanol, isopropanol or tert-butanol, ethers, such as tetrahydrofuran or dioxane, or hydrocarbons, such as benzene, toluene or xylene. The reaction is generally carried out at temperatures of 10 to 100 ° C, in particular at 20 to 60 ° C.

The amino ketones, after conversion of the acid addition salts, for example the hydrochloride of the formula XIII, with bases to the free amines, can be acylated to the amides of the formula XIV in which r ⁴ can represent the phenyl radical described in the above definition of A; C = O) may then remain in the molecule or compounds in which the group R 4 - (C = O) functions as a protecting group, and is cleaved again in the course of the synthesis.

In the latter case, R 1 is, for example, C 1 -C 4 alkyl or trihalomethyl, for example trifluoromethyl. Suitable acylating agents for the amino group are, for example, alkyl esters, halides (e.g. chlorides or bromides) or carboxylic acid anhydrides. In particular, the acylation may be carried out with compounds of the formula R- (C = O) -Y, in which, as shown in Scheme I, the radical R represents, for example, a C1-C4 alkyl group, a trihalomethyl group or a phenyl group which is unsubstituted or substituted by up to three identical or different substituents selected from the group consisting of halogen atoms, alkyl groups of 1 or 2 carbon atoms, and Y represents a leaving group such as halogen, C1-C4alkoxy, trihaloacetoxy or alkylcarbonyloxy 4 carbon atoms in the alkyl moiety.

Syntheses of compounds of formula XIV may be accomplished, for example, by the addition of a tertiary base, such as pyridine, or

Trialkylamine, and in the presence or absence of an inert solvent, whereby a catalyst, for example dimethylaminopyridine, may also be present. The reaction is generally carried out at temperatures of 0 to 160 ° C, in particular 20 to 100 ° C. Suitable inert solvents are, for example, ethers such as tetrahydrofuran or dioxane, glycol ethers such as ethylene glycol monomethyl ether or ethylene glycol monoethyl ether (methyl glycol or ethyl glycol), ethylene glycol dimethyl ether or diglyme, ketones such as acetone or butanone, nitriles such as acetonitrile, amides such as dimethylformamide, N-methylpyrrolidone or hexamethylphosphoric triamide, sulfoxides such as dimethylsulfoxide, chlorinated hydrocarbons such as dichloromethane, chloroform, dichloromethane, 1,2-dichloroethylene or carbon tetrachloride, and hydrocarbons such as benzene, toluene or xylene. Mixtures of these solvents with one another are also suitable.

The chromanones of formula XIV can be reduced to the corresponding chromanols of formula XV by known methods, for example using alkali metal borohydrides such as sodium borohydride or potassium borohydride in alcohols such as methanol or ethanol (Bull. Soc. Chim. Fr. 1972, 3183). .

The chromanones of formula XIV as well as the chromanols of formula XV can be reduced, for example, by catalytic hydrogenation to the amidochromans of formula XVI. Suitable catalysts for this hydrogenation are, for example, metals such as platinum, palladium, rhodium, ruthenium or Raney nickel, wherein the first four metals may also be in the form of their oxides. Preference is given to using palladium, platinum and Raney nickel. Suitable solvents for the hydrogenation are, for example, alcohols such as methanol, ethanol or propanol, ethers such as dioxane or tetrahydrofuran or acids, with acetic acid being preferred. A catalytic amount of a strong acid such as concentrated sulfuric acid, hydrochloric acid, perchloric acid or trifluoroacetic acid can be added during the hydrogenation to accelerate the reaction. The hydrogenation is generally carried out at a temperature of 10 to 50 ° C, in particular at a temperature of 15 to 30 ° C, and at a hydrogen pressure of 0 to 10 MPa, in particular a pressure of 0 to 0.5 MPa (J. Med. Chem. 15, 863). 865 (1972)). If acetic acid is used as the solvent, the yields can be increased by the addition of C1 -C4 alkylcarboxylic anhydrides, such as acetic anhydride. Chromanols of formula XV can also be converted to amidochromans of formula XVI by other reduction methods as described, for example, in Larock, Comprehensive Organic Transformations, VCH, 1989, p. 27 to 28.

The following stages of the synthesis of compounds of formula I are shown in Scheme II.

Scheme II

(XVIIa)

R ⁴ represents a phenyl group which is unsubstituted or substituted by up to three identical or different substituents selected from the group consisting of halogen atoms, alkyl groups of 1 or 2 carbon atoms and alkoxy groups of 1 or 2 carbon atoms, or alkyl groups of 1 to 4 atoms carbon or trihalomethyl group,

R ⁵ may have any of the above meanings of A, or is C 1 -C 4 alkyl, carbon or trihalomethyl.

If the acyl group R- (C = O) in the compounds of formula XVI is a protective group, this group can be cleaved again with bases or acids to give aminochromans of formula XVII. If the cleavage is carried out with acids, for example aqueous acid solutions or acid solutions in inert organic solvents, an appropriate acid addition salt, for example the hydrochloride of the general formula XVIIa, may be formed. For example, sulfuric acid, hydrohalic acids such as hydrochloric or hydrobromic acid, phosphoric acids such as orthophosphoric acid or polyphosphoric acid, or other common acids with which amides can be cleaved, such as organic carboxylic, sulfonic or sulfuric acids, such as is, for example, acetic acid, salicylic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid or lauryl sulfuric acid. The cleavage of the acylated amine of formula XVI with bases can also take place in an aqueous medium or in an inert organic solvent. Suitable bases are, for example, alkali and alkaline earth metal hydroxides or alkoxides, such as sodium hydroxide, potassium hydroxide, calcium hydroxide, sodium methoxide, sodium ethoxide, potassium methoxide or potassium ethoxide.

The amines of formula XVII contain one or two chiral centers on the six-ring carbon atoms. When present as mixtures of stereoisomeric forms, for example as racemates, and if the compounds of formula I are to be prepared in the form of pure stereoisomers, the resolution of the individual stereoisomers may be carried out at the amine stage of formula XVII. If the amines of formula XVII contain two or more centers, they can be formed in the synthesis as mixtures of racemates from which the individual racemates in pure form can be isolated, for example, by recrystallization from inert solvents. The racemates obtained can, if desired, be resolved into the individual enantiomers mechanically or chemically by known methods. Thus, individual diastereomers can be obtained from the racemate by reaction with an optically active resolving agent. Suitable resolving agents for basic compounds are, for example, optically active acids, such as the R-, optionally R, R- and S- or S-, S-forms of tartaric acid, dibenzoyltartaric acid, diacetyltartaric acid, camphorsulfonic acid, mandelic acid, malic acid or lactic acid. The various forms of diastereomers may be resolved in a known manner, for example by fractional crystallization, and the enantiomers may be liberated from the diastereomers in a known manner. The resolution of enantiomers can further be carried out by chromatography on optically active carriers. A particularly simple process for the preparation of optically uniform compounds consists in the corresponding substitution, for example, by cleaving the amines of the general formula (XVII) by means of crystallization or recrystallization of salts with optically active acids such as (+) - or (-) mandelic acid. and these are converted to the final compounds of formula I, which in turn are enantiomerically pure. However, in the preparation of stereochemically uniform compounds of formula I, for example, pure enantiomers, cleavage using the above methods or other conventional methods may also be carried out at other stages of the synthesis.

Compounds of formula XVII, including stereochemically uniform forms, can be acylated to amides of formulas XVIa and XVI, respectively. As acylating agents for introducing an AC (= O) group in which A is a phenyl group which is unsubstituted or substituted by up to three identical or different substituents selected from the group consisting of halogen atoms, alkyl groups having 1 or 2 carbon atoms and alkoxy groups having 1 or 2 2 carbon atoms which may remain in the molecule are, for example, alkyl esters, halides (e.g. chlorides or bromides) or benzoic anhydrides suitable. In particular, acylation may be accomplished using compounds of formula AC (= O) -Y, wherein A is a phenyl group which is unsubstituted or substituted with up to three of the same or different substituents selected from the group consisting of halogen atoms, alkyl groups having 1 or 2 carbon atoms and alkoxy having 1 or 2 carbon atoms, and Y represents a leaving group such as a halogen atom, a C1-4 alkoxy group, a trihaloacetoxy group or a C1-4 alkylcarbonyloxy group in the alkyl moiety. This acylation may in turn be carried out by the addition of tertiary bases such as pyridine or trialkylamines and in the presence or absence of an inert solvent, and a catalyst such as dimethylaminopyridine may also be present. The reaction is generally carried out at temperatures of 0 to 160 ° C, in particular at 20 to 100 ° C. Suitable inert solvents are, for example, ethers such as tetrahydrofuran or dioxane, glycol ethers such as ethylene glycol monomethyl ether or ethylene glycol monoethyl ether (methyl glycol or ethyl glycol) , ethylene glycol dimethyl ether or diglyme, ketones such as acetone or butanone, nitriles such as acetonitrile, amides such as dimethylformamide, N-methylpyrrolidine or hexamethylphosphoric triamide, sulfoxides such as dimethylsulfoxide, chlorinated hydrocarbons such as dichloromethane, dichloromethane, 1,2-dichloroethane or carbon tetrachloride; and hydrocarbons such as benzene, toluene or xylene. Mixtures of these solvents with one another are also suitable.

Compounds of formula XVIa wherein A is a radical of formula

Ek / N

I or one of the radicals of the general formulas

can be prepared, for example, according to the following methods. According to one method, the amine of formula XVII is first converted to an isocyanate of formula XVIII by a known method by reaction with a carbonic acid halide such as phosgene or triphosgene in the presence of a tertiary alkylamine or pyridine and an inert solvent.

2

R

(XVIII) wherein R1, R2a, R2b, _and R2c are as defined above. Suitable inert solvents are, for example, ethers such as tetrahydrofuran, dioxane, ethylene glycol dimethyl ether or diglyme, ketones such as acetone or butanone, nitriles such as acetonitrile, nitro compounds such as nitromethane, esters such as ethyl acetate, amides such as dimethylformamide, N-methylpyrrolidine or hexamethylphosphoric triamide, sulfoxides such as dimethyl sulfoxide, sulfones such as sulfolane, and hydrocarbons such as benzene, toluene or xylene. Mixtures of these solvents with one another are also suitable. According to another method, the amines of formula XVII are first converted into reactive carbonic acid derivatives, for example carbonic acid esters (urethanes) in a known manner. They can be synthesized from alkyl chloroformates and amines of formula XVII in the presence of suitable tertiary alkylamines or pyridine. Further, N, N'-carbonyldiimidazole and analogous reactive intermediates (HA Staab, Synthesen mit Heterocyclic Amen (Azoliden), Angewandte Chemie 74, 407 423 (1962)) can also be used as alkoxy equivalents of isocyanates.

Isocyanates of formula XVIII, urethanes or intermediates obtained from amines of formula XVII and, for example, N, N'-carbonyldiimidazole can then be reacted with a compound of formula

ABOUT

in which B is as defined above, or with a compound of one of the formulas

in the presence or absence of an inert solvent at temperatures of 100-170 ° C (Justus Liebigs Ann. Chem. 598, 203 (1956)) to give the corresponding compounds of formula XVIa wherein A is one of the heterocyclic radicals.

From the acylated amines of the formulas XVI and XVIa, sulfonamides of the formula I can be prepared in a manner known per se using suitable and known reaction conditions.

Illa (cf. Scheme II). It is also possible to use known but not described variants. The sulfonamide syntheses may be carried out in one, two or more stages. Particularly preferred are processes in which the acylated amines of formula XVI or XVIa are converted to aromatic β by electrophilic reagents in the presence or absence of inert solvents at temperatures of -10 to 120 ° C, preferably at temperatures of 0 to 100 ° C. -chromanylsulfonic acids or derivatives thereof, for example sulfonic acid halides of the formula VIIa. For example, sulfonations with sulfuric acid or fuming sulfuric acid, halosulfonation with halosulfonic acids such as chlorosulfonic acid, reaction with sulfuryl halides in the presence of anhydrous metal halides, or reaction with thionyl halides in the presence of anhydrous metal halides with the subsequent metal halide with subsequent sulfonation . If the primary reaction products are sulfonic acids, they may be either directly or after reaction with tertiary amines, for example pyridine or trialkylamines, or with alkali or alkaline earth metal hydroxides or with reagents which form these basic compounds in situ, in a known manner with acid halides, such as phosphorous halides, phosphorous halides, phosphorus oxychloride, thionyl halides or oxalyl halides, to be converted to sulfonic acid halides, for example of the general formula VIIa. The conversion of the sulfonic acid derivatives to the sulfonamides of the formula IIIa is carried out by methods known from the literature, in particular the sulfonic acid chlorides are reacted with aqueous ammonia in inert solvents at temperatures of 0 to 100 ° C.

In the synthesis of the compounds of the formula I, the corresponding sulfonamides of the formula IIIa can also be prepared from the acylated amines of the formula XVI in which the group R 1 -C (= O) has the function of a protecting group. As shown in Scheme II, R 1 may be present in the general formulas

VIIIa and IIIa, any of the above meanings of A or may, as well as r4, represent, for example, an alkyl group having 1 to 4 carbon atoms or a trihalomethyl group. When the symbol in the formula IIIa has the meaning of the symbol A, they are compounds of the formula III. When R1 in formula IIa is A, they are compounds of formula VIII.

From the compounds of formula (IIIa) which contain a protecting group, this protecting group may be cleaved after the introduction of the sulfonamide moiety by means of acids or bases as described above for the cleavage of the protecting group from compounds of formula (XVI). From the sulfonamidesubstituted amines thus prepared, sulfamoylchromans of formula III can be prepared as described above for the introduction of the AC (= O) group into compounds of formula XIII or XVII. According to the nature of the substituents R, R 2, RZB, _t r 3 _of R 2c and Z may be any of the above methods and embodiments are less suitable for the synthesis of compounds of formula I, or at least be made for the protection of reactive groups. However, such relatively rare occurrences are readily recognized by one of ordinary skill in the art, and in such cases another of the described synthetic methods can be used without difficulty.

The compounds of formula I affect the action potential of cells, particularly cardiac muscle cells. They exhibit a normalizing effect on impaired action potential, which occurs, for example, in ischemia, and are therefore suitable, for example, for the treatment and prophylaxis of cardiovascular disorders, in particular arrhythmias and their consequences. The activity of the compounds of formula I can be demonstrated, for example, in the model described below, which determines the duration of action potential on guinea pig papillary muscle.

Thus, the compounds of formula I and their physiologically acceptable (harmless) salts can be used alone, in admixture with each other or in the form of pharmaceutical preparations, as medicaments for animals, preferably mammals, and especially humans. Animals which can be used or tested for compounds of formula I are, for example, monkeys, dogs, mice, rats, rabbits, guinea pigs, cats and larger livestock such as cattle and pigs. The present invention also relates to compounds of the formula I and / or their physiologically acceptable salts for use as medicaments, as well as pharmaceutical preparations which contain, in addition to the usual pharmaceutically acceptable carriers and excipients, an effective dose of at least one compound of the formula I and / or physiologically acceptable salts. The pharmaceutical preparations may be intended for enteral or parenteral use and contain normally 0.5 to 90% by weight of the compounds of the formula I and / or their physiologically acceptable salts.

The pharmaceutical compositions of the invention may be prepared in a manner known per se. In this connection, the compounds of the formula I and / or their physiologically acceptable salts together with one or more solid or liquid carriers or excipients and, if desired, in combination with other medicaments, for example medicaments acting on the cardiovascular system, such as calcium antagonists or ACE-inhibitors, will be made into a suitable dosage and dosage form which can then be used as a medicament in human or veterinary medicine.

Suitable carriers are organic or inorganic substances which are suitable, for example, for enteral (e.g. oral) administration, parenteral administration (e.g. intravenous injection or infusion) or for topical use, and do not react with compounds of the formula I, e.g. water, vegetable oils , waxes, alcohols such as ethanol, propanediol or benzyl alcohol, glycerol, polyols such as polyethylene glycol or polypropylene glycol, glycerol triacetate, gelatin, carbohydrates such as lactose or starches, stearic acid and its salts such as magnesium stearate, talc, lanolin or Vaseline. For oral and rectal administration, particular dosage forms such as tablets, dragees, capsules, suppositories, solutions, in particular oily and aqueous solutions, syrups, juices or drops, and suspensions or emulsions are used. Ointments, creams, pastes, lotions, gels, sprays, foams, aerosols, solutions or powders are particularly suitable for topical use. As solvents for the solutions, for example, alcohols such as ethanol, isopropanol or 1,2-propanediol or mixtures thereof or mixtures with water may be used. Other dosage forms are, for example, implants. The compounds of formula (I) may also be lyophilized and the lyophilizates obtained used, for example, for the preparation of injectables. Liposomal formulations are also suitable, in particular for topical use. The pharmaceutical preparations may contain excipients such as glidants, preservatives, pickling agents, thickeners, stabilizers and / or wetting agents, sustained release agents, emulsifiers, salts (e.g., for influencing osmotic pressure), buffering agents, coloring agents, flavoring agents and / or flavoring agents: These preparations may also contain, if desired, one or more other active substances and / or, for example, one or more vitamins.

The compounds of formula I and their physiologically acceptable salts are effective therapeutic agents which are useful not only as antiarrhythmic agents, but also for the treatment and prophylaxis of other cardiovascular disorders, cardiac insufficiency, ischemia, heart transplantation or cerebral vascular disease in man or in human mammals. In particular, the compounds of the invention find use as antiarrhythmic agents for the treatment of cardiac arrhythmias of various origins and for the prevention of arrhythmically related sudden cardiac death. Examples of arrhythmic cardiac disorders include supraventricular rhythm disorders such as atrial tachycardia, atrial oscillation, or paroxysmal supraventricular rhythm disorders, or ventricular rhythm disorders such as ventricular extrasystoles, but in particular life-threatening ventricular tachycardia or particularly fibrillar ventricular dysfunction. The compounds of the invention are particularly useful in cases where the arrhythmias result from a coronary artery constriction, which occurs, for example, in angina or during an acute heart attack or is a chronic consequence of a heart attack.

They are therefore particularly suitable for patients after a heart attack to prevent sudden cardiac death. Other diseases in which such rhythm disorders and / or sudden arrhythmia-related cardiac death play a role are, for example, cardiac insufficiency or cardiac hypertrophy as a result of chronically elevated blood pressure.

In addition, the compounds of the invention are capable of positively affecting reduced cardiac contractility and attenuated cardiac output. These can be diseases due to the weakening of the contractility of the heart, such as, for example, cardiac insufficiency, but also acute cases such as heart failure due to shock. This is how the heart can re-start its performance more quickly and reliably after successful transplantation. The same is true for cardiac operations where temporary cardiac arrest with cardioplegic solutions is required.

The invention also relates to the use of the compounds of the formula I and / or their physiologically acceptable salts for the treatment and prophylaxis of the diseases mentioned above, and their use for the preparation of medicaments for use in these diseases.

For example, the dosages required to treat cardiac arrhythmias with the compounds of Formula I depend on whether acute or prophylactic therapy is conducted and is determined by the circumstances of the particular case. For prophylaxis, a dose in the range of at least about 0.01 mg, preferably 0.1 mg, in particular 1 mg to a maximum of 100 mg, preferably 10 mg per kg per day is normally suitable. A dosage range of from 1 to 10 mg per kg per day is particularly suitable. The dose may be administered in the form of a single oral or parenteral dose or may be divided into several, for example two, three or four, individual doses. When treating acute cases of cardiac rhythm disorders, for example in an intensive care unit, parenteral administration, for example by injection or infusion, may be advantageous. The preferred dose range in critical situations may then be 10 to 100 mg per kg per day and may be administered, for example, by intravenous long-term infusion.

The compounds of formula I inhibit ATP sensitive potassium channels of cells. In addition to their use as active substances for pharmaceuticals in human and veterinary medicine, the compounds of the formula I can also be used as scientific tools or as auxiliaries in biochemical studies in which such ion channel treatment is desirable as well as for diagnostic purposes. Furthermore, the compounds of the formula I and their salts can be used as intermediates for the preparation of further active compounds for pharmaceuticals.

For example, the following compounds of formula I can be obtained analogously to the compounds described in the Examples below:

3- (5-chloro-2-methoxybenzamido) -6- (methylaminocarbonylaminosulfonyl) -7-ethylchromane,

3- (5-chloro-2-methoxybenzamido) -6- (methylaminocarbonylaminosulfonyl) -7-ethoxychroman.

3- (5-bromo-2-methoxybenzamido) -6- (methylaminocarbonylaminosulfonyl) -7-ethylchromane,

3- (5-bromo-2-methoxybenzamido) -6- (methylaminocarbonylaminosulfonyl) -7-methoxy-chroman,

3- (5-chloro-2-methoxybenzamido) -6- (ethylaminocarbonylaminosulfonyl) -7-ethylchromane,

3- (5-bromo-2-methoxybenzamido) -6- (ethylaminocarbonylaminosulfonyl) -7-ethylchromane,

3- (5-chloro-2-methoxybenzamido) -6- (ethylamino) -7-ethoxychroman.

3- (5-bromo-2-methoxybenzamido) -6- (ethylaminothiocarbonylaminosulfonyl) -7-methoxychroman,

3- (3-ethyl-4-methyl-2-oxo-3-pyrroline-l-carboxamido) -6- (methylaminocarbonylaminosulfonyl) -7-ethoxychroman.

3- (3-ethyl-4-methyl-2-oxo-3-pyroline-1-carboxamido) -6- (methylaminocarbonylaminosulfonyl) -7-ethoxychroman,

3- (3-ethyl-4-methyl-2-oxo-3-pyroline-1-carboxamido) -6- (methylaminocarbonylaminosulfonyl) -7-ethylchroman,

3- (3-ethyl-4-methyl-2-oxo-3-pyrroline-l-carboxamido) -6- (methylaminocarbonylaminosulfonyl) -7-ethylchromane,

3- (2-oxo-3-pyrroline-l-carboxamido) -6- (methylaminocarbonylaminosulfonyl) -7-ethoxychroman.

3- (2-oxo-3-pyrroline-l-carboxamido) -6- (methylaminocarbonylaminosulfonyl) -7-ethoxychroman.

3- (2-oxo-3-pyroline-1-carboxamido) -6- (methylaminothiocarbonylaminosulfonyl) -7-ethylchroman and

3- (2-oxo-3-pyrroline-l-carboxamido) -6- (methylaminocarbonylaminosulfonyl) -7-ethylchromane.

3- (2-oxo-3-pyrroline-l-carboxamido) -6- (methylaminocarbonylaminosulfonyl) -7-ethoxychroman.

3- (2-oxo-3-pyrroline-l-carboxamido) -6- (methylaminocarbonylaminosulfonyl) -7-ethoxychroman.

DETAILED DESCRIPTION OF THE INVENTION

Example 1

3- (5-chloro-2-methoxybenzamido) -6- (methylaminocarbonylaminosulfonyl) -7-methoxychroman

1.71 g (4 mmol) of 3- (5-chloro-2-methoxybenzamido) -6-sulfamoyl-7-methoxychroman in 10 ml of dry dimethylsulfoxide were added, after addition of 0.4 g (10 mmol) of freshly ground sodium hydroxide and 1.05 g. (6 mmol) of N-methyltrichloroacetamide was heated at 80 ° C for 30 min. The cooled reaction mixture was poured into ice water, clarified with activated carbon and acidified to pH 1. The precipitate was filtered off with suction, dried and recrystallized twice from ethanol. Melting point 256-257 ° C.

Preparation of the starting compound 3- (5-chloro-2-methoxybenzamido) -6-sulfamoyl-7-methoxychroman

15.1 g (70 mmol) of 3-amino-7-methoxychroman hydrochloride (Eur. J. Med. Chem. 11, 251-256 (1976)) are dissolved in 80 ml of pyridine and 14 is added at 0 ° C. , 8 g of 2-methoxy-5-chlorobenzoic acid chloride. The mixture was stirred at room temperature for 1.5 hours and at 60 ° C for 1 hour. The cooled reaction mixture was partitioned between water and dichloromethane. The aqueous phase is extracted three times with dichloromethane and the combined organic phases are washed with 2 N hydrochloric acid, water and sodium bicarbonate solution. After drying and evaporation of the organic phase, the residue is dissolved in a small amount of toluene and precipitated with an excess of diethyl ether. 3- (5-chloro-2-methoxybenzamido) -7-methoxychroman is obtained, m.p. 92-93 ° C.

3- (5-chloro-2-methoxybenzamido) -7-methoxychroman (g) was added portionwise with stirring to 35 ml of chlorosulfonic acid cooled to -10 ° C. The temperature was then allowed to rise to room temperature and an additional 5 ml of acid was added. chlorosulphonic. After stirring for 1 hour, the reaction mixture was carefully stirred into ice water. The precipitate obtained is filtered off with suction and, after washing with water, is introduced into a mixture of 200 ml of acetone and 120 ml of concentrated aqueous ammonia solution cooled to -20 [deg.] C. The temperature is then allowed to rise to room temperature. Concentrated hydrochloric acid is added to the residue under ice-cooling, the precipitate obtained is filtered off with suction and recrystallized from a mixture of glacial acetic acid and methanol. The obtained 3- (5-chloro-2-methoxybenzamido) -6-sulfamoyl-7-methoxychroman has a melting point of 210 212 ° C.

Example 2

3- (5-chloro-2-methoxybenzamido) -6- (ethylaminocarbonylaminosulfonyl) -7-methoxy-chroman

This material was prepared in an analogous manner to Example 1, substituting 1.15 g (6 mmol) of N-ethyltrichloroacetamide for N-methyltrichloroacetamide. The product melted at 233-234 ° C after recrystallization from ethanol.

Example 3

3- (5-chloro-2-methoxybenzamido-6- (n-propylaminocarbonylaminosulfonyl) -7-methoxychroman

II ^HH

C ₃ H ₇

This material was prepared in a manner analogous to Example 1, substituting 1.23 g (6 mmol) of N-n-propyltrichloroacetamide for N-methyltrichloroacetamide. Mp 203-205 ° C after recrystallization from ethyl acetate.

Example 4

3- (5-chloro-2-methoxybenzamido) -6-izopropylaminokarbonylaminosulfonyl) -7-methoxy-chroman ^^. _OCH3

o ch ₃

Λ A

N CH ₃ HH

This material was prepared in a manner analogous to Example 1, substituting (6 mmol) N-isopropyltrichloroacetamide for N-methyltrichloroacetamide. Example 1.23 g of product after recrystallization from methanol is 181-183 ° C.

Example 5

3- (5-chloro-2-methoxybenzamido) -6- (n-butylaminokarbonylaminosulfonyl) -7-methoxy-chroman / \ / ^0CH 3

This material was prepared in an analogous manner to Example 1 using 1.31 g (6 mmol) of N-butyltrichloroacetamide instead of N-methyltrichloroacetamide. Melting point: 185-186 ° C after recrystallization from methanol.

Example 6

3- (5-chloro-2-methoxybenzamido) -6- (methylaminothiocarbonylaminosulfonyl) -7-methoxychroman

1.71 g (4 mmol) of 3- (5-chloro-2-methoxybenzamido) -6-sulfamoyl-7-methoxychroman (see Example 1) were dissolved in 10 ml of dry dimethylsulfoxide and 1.65 g (12 mmol) was added. finely ground potassium carbonate and 0.35 g (4.8 mmol) of methyl isothiocyanate. The mixture is stirred for 25 minutes at 80 ° C, then cooled, poured into water, clarified with charcoal and acidified to pH 1. The precipitate is filtered off with suction, dried and recrystallized from a mixture of ethanol and dimethylformamide. Melting point: 219-220 ° C.

Example 7

3- (5-chloro-2-methoxybenzamido) -6- (ethylaminothiocarbonylaminosulfonyl) -7-methoxychroman

^{H H}

C ₂ H ₅

This material was prepared in a manner analogous to Example 6, substituting 0.41 g (4.8 mmol) of ethyl isothiocyanate for methyl isothiocyanate. Melting point: 194-195 ° C after recrystallization from methanol / dimethylformamide.

Example 8

3- (5-chloro-2-methoxybenzamido) -6- (n-propylaminothiocarbonylaminosulfonyl) -7-methoxychroman

This material was prepared in a manner analogous to Example 6, substituting 0.5 ml (4.8 mmol) of n-propylisothiocyanate for methyl isothiocyanate. The product melts at 182 DEG C. after recrystallization from methanol / dimethylformamide.

Example 9

3- (5-fluoro-2-methoxybenzamido) -6- (methylaminocarbonylaminosulfonyl) -7-methoxychroman

1.64 g (4 mmol) of 3- (5-fluoro-2-methoxybenzamido) -6-sulfamoyl-7-methoxychroman in 10 ml of dry dimethylsulphoxide were added after addition of 0.4 g (10 mmol) of freshly ground sodium hydroxide and 1, The N-methyltrichloroacetamide (05 g, 6 mmol) was heated at 80 ° C for 30 min. The cooled reaction mixture was poured into ice water, clarified with charcoal and acidified to pH 1. The precipitate was filtered off with suction, dried and recrystallized from ethanol. Mp 260 ° C.

Preparation of the starting compound 3- (5-fluoro-2-methoxybenzamido) -6-sulfamoyl-7-methoxychroman

To a solution of 15.1 g (70 mmol) of 3-amino-7-methoxychroman hydrochloride in 80 mL of pyridine cooled to 0 ° C was added 13.6 g (72 mmol) of 2-methoxy-5-fluorobenzoic acid chloride. The work-up is carried out analogously to Example 1. The obtained 3- (5-fluoro-2-methoxybenzamido) -7-methoxychroman, after recrystallization from ethanol, has a melting point of 107-108 ° C. Example 1. The obtained 3- (5-fluoro-2-methoxybenzamido) -6-sulfamoyl-7-methoxychroman has a melting point of 209-210 ° C after recrystallization from a mixture of dimethylformamide and methanol.

Example 10

3- (5-fluoro-2-methoxybenzamido) -6- (methylaminocarbonylaminosulfonyl) -7-methoxy-chroman ^^ / ^0CH 3

H H

HN

To a solution of 1.64 g (4 mmol) of 3- (5-fluoro-2-methoxybenzamido) -6-sulfamoyl-7-methoxychroman (see Example 9) in 10 mL of dry dimethyl sulfoxide was added 1.65 g (12 mmol) of ground potassium carbonate and 0.35 g (4.8 mmol) of methyl isothiocyanate. The mixture was heated at 80 ° C for 25 minutes, then cooled, poured into water, clarified with charcoal and acidified to pH 1. The precipitate was filtered off with suction, dried and recrystallized from ethanol. Mp 221-222 ° C.

Example 11

3- (5-fluoro-2-methoxybenzamido) -6- (ethylamino) -7-methoxy-chroman

This material was prepared in an analogous manner to Example 10, using 0.41 g (4.8 mmol) of ethyl isothiocyanate instead of methyl isothiocyanate. Melting point: 186-187 ° C.

Example 12

3- (5-fluoro-2-methoxybenzamido) -6- (n-propylaminothiocarbonylaminosulfonyl-7-methoxychroman)

C3H7

This material was prepared in an analogous manner to that of Example 10 using 0.5 ml (4.8 mmol) of n-propylisothiocyanate instead of methyl isothiocyanate. The melting point of the product after recrystallization from ethanol is 172-173 ° C.

Example 13

3- (5-fluoro-2-methoxybenzamido) -6- (isopropylaminothiocarbonylaminosulfonyl) -7-methoxychroman

ch ₃ as in the example

This material was prepared in an analogous manner to 10 using 0.48 ml (4.8 mmol) of n-propylisothiocyanate instead of methyl isothiocyanate. Melting point: 179-180 ° C after recrystallization from ethanol.

Example 14

3- (5-chloro-2-methoxybenzamido) -6- (methylaminothiocarbonylaminosulfonyl) -7-methylchroman

1.64 g (4 mmol) of 3- (5-chloro-2-methoxybenzamido) -6-sulfamoyl-7-methylchroman are dissolved in 10 ml of dry dimethylsulfoxide and 1.65 g (12 mmol) of finely ground potassium carbonate are added and 0.35 g (4.8 mmol) of methyl isothiocyanate. The mixture is heated at 80 ° C for 25 minutes, then cooled, poured into ice water, clarified with charcoal and acidified to pH 1. The precipitate is filtered off with suction, dried on a silica gel column, eluting with a mixture of ethyl acetate / toluene (2: 1) and recrystallized from ethanol. Melting point: 207-208 ° C.

Preparation of the starting compound 3- (5-chloro-2-methoxybenzamido) -6-sulfamoyl-7-methylchroman

a) 3- (5-chloro-2-methoxybenzamido) -7-methyl-4-chromanone

To a solution of 18.2 g (85 mmol) of 3-amino-7-methyl-4-chromanone hydrochloride (Hebd. Seances Acad. Sci., Ser. C 279, 281-284) in 90 ml of pyridine is added 17 at room temperature. 5 g (85 mmol) of 5-chloro-2-methoxybenzoyl chloride. After stirring for 2 hours under thin layer chromatography on a silica gel plate using petroleum ether / ethyl acetate / toluene 2: 2: 1 as the eluent, the reaction mixture was poured into ice / water. The precipitate formed is filtered off with suction, washed several times with water and dried. The melting point of 3- (5-chloro-2-methoxybenzamido) -7-methyl-4-chromanone is 177-178 ° C.

b) 3- (5-chloro-2-methoxybenzamido) -7-methyl-4-chromanol

To a suspension of 8.65 g (25 mmol) of 3- (5-chloro-2-methoxybenzamido) -7-methyl-4-chromanone in 40 ml of ethanol was added 0.5 g (12.5 mmol) of sodium borohydride. During stirring at 30-40 ° C for two hours, the solid goes into solution. The solution is cooled, poured into ice-water and acidified to pH 1-2 with dilute hydrochloric acid. The precipitate formed is filtered off with suction, washed with water, dried and recrystallized from ethanol. The melting point of 3- (5-chloro-2-methoxybenzamido) -7-methyl-4-chromanol as a mixture of two diastereomers is 151-152 ° C.

c) 3- (5-chloro-2-methoxybenzamido) -7-methylchroman

7.7 g (22 mmol) of 3- (5-chloro-2-methoxybenzamido) -7-methyl-4-chromanol in a mixture of 80 ml of glacial acetic acid, 7.5 ml of acetic anhydride and 0.5 ml of trifluoroacetic acid 0.5 g of 10% palladium on carbon is hydrogenated for about 3 hours at 25 ° C and atmospheric pressure. The catalyst is filtered off, the filtrate is concentrated in vacuo to a small volume. The residue was taken up in ice-water and extracted several times with dichloromethane. The combined dichloromethane extracts were washed with sodium bicarbonate solution and water, dried and concentrated, and the residue was recrystallized from diisopropyl ether. The melting point of 3- (5-chloro-2-methoxybenzamido) -7-methylchroman is 97 ° C.

d)

3- (5-chloro-2-methoxybenzamido) -6-sulfamoyl-7-methylchroman

5.8 g of 3- (5-chloro-2-methoxybenzamido) -7-methylchroman were stirred into 10 ml of chlorosulfonic acid with gentle cooling. After stirring at room temperature for 45 minutes, the reaction mixture was carefully added dropwise to an ice / water mixture. The precipitate was filtered off with suction and added to a mixture of 50 ml of acetone and 30 ml of concentrated aqueous ammonia solution cooled to -10 ° C. The mixture was allowed to warm to room temperature and after stirring for 3 hours the solution was concentrated in vacuo at 30 ° C. cooling with ice, the residue is acidified with concentrated hydrochloric acid. The precipitate is filtered off with suction, washed with water to neutral pH and recrystallized from a mixture of glacial acetic acid and methanol. The melting point of 3- (5-chloro-2-methoxybenzamido) -6-sulfamoyl-7-methylchroman is 218-219 ° C.

Example 15

3- (5-Chloro-2-methoxybenzamido) -2,2-dimethyl-6 (methylaminocarbonylaminosulfonyl) -7-methoxychroman

To 2.27 g (5 mmol) of 3- (5-chloro-2-methoxybenzamido) -2,2-dimethyl-6-sulfamoyl-7-methoxychroman and 0.5 g (12.5 mmol) of finely ground sodium hydroxide are added 1. 23 g (7.5 mmol) of N-methyltrichloroacetamide. After stirring at 80 ° C for half an hour, the mixture is poured into ice-water, clarified with charcoal and acidified to pH 1. The precipitate formed is filtered off with suction, dried and recrystallized from a mixture of ethanol and dimethylformamide. Mp 248 ° C.

Preparation of the starting compound 3- (5-chloro-2-methoxybenzamido) -2,2-dimethyl-6-sulfamoyl-7-methoxychroman

a) 2,2-Dimethyl-7-methoxy-4-chromanone oxime tosyl acetate

To a solution of 88.5 g (0.4 mol) of 2,2-dimethyl-7-methoxy-4-chromanone oxime (Heterocycles 38, 305-318 (1994)) in 550 mL of pyridine at 0 ° C is added 85.8 g (0.45 mol) of ptoluenesulfonic acid chloride. The mixture was allowed to warm to room temperature, stirred for several hours, poured into ice / water and extracted with dichloromethane. The organic phase is washed twice with 2 N hydrochloric acid and several times with water, dried and evaporated in vacuo, and the residue is recrystallized from ethanol. The melting point of 2,2-dimethyl-7-methoxy-4-chromanone oxime tosylate is 113 ° C.

b) 3-amino-2,2-dimethyl-7-methoxy-4-chromanone hydrochloride

6.9 g (0.3 mol) of sodium are dissolved in 250 ml of ethanol under gentle cooling under nitrogen. To the thus prepared sodium ethoxide solution, a suspension of 105 g (0.28 mol) of 2,2-dimethyl-7-methoxy-4-chromanone oxime tosylate in 900 ml of ethanol is added and the mixture is heated at 50 ° C for 3 hours and temperature 60 °

C for 1 hour. After cooling, the precipitated sodium sulfonate is filtered off with suction, the filtrate is concentrated, poured into ice-free salt-free water, extracted twice with dichloromethane and the aqueous solution is clarified with charcoal. Concentration yields

3-Amino-2,2-dimethyl-7-methoxy-4-chromanone hydrochloride, m.p. 224-226 ° C.

c) 3- (5-chloro-2-methoxybenzamido) -2,2-dimethyl-7-methoxy-4-chromanone

To a solution of 33.5 g (0.13 mol) of 3-amino-2,2-dimethyl-7-methoxy-4-chromanone hydrochloride in 150 ml of pyridine is added 28.7 g (0.14) at 10 ° C. mol) of 5-chloro-2-methoxybenzoyl chloride. After stirring at room temperature for 3 hours, the reaction mixture was poured into ice-water and extracted twice with dichloromethane. The combined dichloromethane extracts were washed twice with 2 N hydrochloric acid and water, dried and evaporated. The residue is recrystallized from a mixture of ethanol and dimethylformamide. The melting point of 3- (5-chloro-2-methoxybenzamido) -2,2-dimethyl-7-methoxychromanone is 174 ° C.

d) 3- (5-chloro-2-methoxybenzamido) -2,2-dimethyl-7-methoxy-4-chromanol

A suspension of 25 g (64 mmol) of 3- (5-chloro-2-methoxybenzamido) -2,2-dimethyl-7-methoxy-4-chromanone and 1.24 g (32 mmol) of ground sodium borohydride in 100 ml of ethanol is stirred for 3 hours at 50 ° C, whereby the solid gradually dissolves. After cooling, the solution was poured into ice-free salt-free water and extracted with dichloromethane. The combined organic layers were washed with water, dried and evaporated. The melting point of 3- (5-chloro-2-methoxybenzamido) -2,2-dimethyl-7-methoxy-4-chromanol as the two diastereomers is 165 ° C.

e) 3- (5-chloro-2-methoxybenzamido) -2,2-dimethyl-7-methoxychroman

To 19.6 g (50 mmol) of 3- (5-chloro-2-methoxybenzamido) -2,2-dimethyl-7-methoxy-4-chromanol in 120 ml of acetonitrile was added 44 g (300 mmol) of sodium iodide and 38 g of sodium iodide. ml (300 mmol) of chlorotrimethylsilane (temperature temporarily rose to 32 ° C). After stirring at room temperature for 3 hours, the mixture was poured into ice-water, decolorized with concentrated sodium bisulfite solution and extracted several times with dichloromethane. The combined organic layers were washed with water, dried and evaporated, and the residue was chromatographed on a silica gel column eluting with dichloromethane: ethyl acetate (95: 5).

3- (5-Chloro-2-methoxybenzamido) -2,2-dimethyl-7-methoxychroman was obtained as an oil.

f) 3- (5-chloro-2-methoxybenzamido) -2,2-dimethyl-7-methoxy-6-sulfamoyl chromate

OCH

0 ^ 0'NH,

H, Cg (47.9 mmol) of 3- (5-chloro-2-methoxybenzamido) -2,2-dimethyl-7-methoxychroman was cooled to below 0 ° C and 25 mL of chlorosulfonic acid cooled to -30 ° C was added. After heating to 10 ° C, the temperature was quickly raised to 35 ° C. The mixture was cooled to 0 ° C, then stirred for 2 hours at 15 ° C and poured into ice water. The precipitated sulfochloride is filtered off with suction and introduced into a mixture of 350 ml of acetone and 75 ml of concentrated aqueous ammonia solution cooled to -10 DEG C. The temperature is allowed to rise to room temperature and the reaction mixture is stirred at this temperature for several hours. After concentration in vacuo at 30 ° C, the residue is acidified with concentrated hydrochloric acid under ice-cooling and the precipitate formed is filtered off with suction, washed with water to neutral pH, dried and recrystallized from ethanol. The melting point of 3- (5-chloro-2-methoxybenzamido) -2,2-dimethyl-7-methoxy-sulfamoylchroman is 228 ° C. Example 16

3- (5-chloro-2-methoxybenzamido) -2,2-dimethyl-6- (methylaminothiocarbonylaminosulfonyl) -7-methoxychroman

'N'

H, CH,

To a suspension of 1.14 g (2.5 mmol) of 3- (5-chloro-2-methoxybenzamido) -2,2-dimethyl-6-sulfamoyl-7-methoxychroman and 1.04 g (7.5 mmol) of finely ground of potassium carbonate in 10 ml of dimethylsulfoxide was added 0.26 g (3.5 mmol) of methyl isothiocyanate. After stirring at 80 ° C for 25 minutes, the mixture is cooled, poured into ice / water, clarified with charcoal and acidified to pH 1. The precipitate is filtered off with suction, dried and recrystallized from a mixture of methanol and dimethylformamide. Melting point 243 245 ° C.

Example 17

3- (5-chloro-2-methoxybenzamido) -2,2-dimethyl-6- (n-propylaminothiocarbonyl aminosulfonyl) -7-methoxychroman

This material was prepared in an analogous manner to that in Example 16 using 0.36 ml (3.5 mmol) of n-propylisothiocyanate instead of methyl isothiocyanate. Melting point: 210-211 ° C after recrystallization from methanol / dimethylformamide.

I

Example 18

3- (5-chloro-2-methoxybenzamido) -2,2-dimethyl-6- (isopropylaminothiocarbonyl aminosulfonyl) -7-methoxychroman

This material was prepared in an analogous manner to that in Example 16 using 0.35 ml (3.5 mmol) of isopropyl isothiocyanate instead of methyl isothiocyanate. Melting point: 210-211 ° C after recrystallization from methanol / dimethylformamide.

Example 19

3- (5-fluoro-2-methoxybenzamido) -2,2-dimethyl-6- (methylaminothiocarbonylaminosulfonyl) -7-methoxy-chroman

F

To a suspension of 1.1 g (2.5 mmol) of 3- (5-fluoro-2-methoxybenzamido) -2,2-dimethyl-6-sulfamoyl-7-methoxychroman and 1.04 g (7.5 mmol) of finely ground of potassium carbonate in 10 ml of dimethylsulfoxide was added 0.26 g (3.5 mmol) of methyl isothiocyanate. After stirring at 80 ° C for 25 minutes, the mixture was cooled, poured into ice / water, clarified with charcoal and acidified to pH 1. The precipitate was filtered off with suction, dried and recrystallized from a mixture of ethanol and dimethylformamide. Melting point 222 ° C.

Preparation of the starting compound 3- (5-fluoro-2-methoxybenzamido) -2,2-dimethyl-6-sulfamoyl-7-methoxychroman

a) 3- (5-fluoro-2-methoxybenzamido) -2,2-dimethyl-7-methoxy-4-chromanone

This material was prepared in an analogous manner to Example 15c using 26.4 g (0.14 mol) of 5-fluoro-2-methoxybenzoyl chloride instead of 5-chloro-2-methoxybenzoyl chloride. The product melts at 143-144 ° C after recrystallization from ethanol / dimethylformamide.

b) 3- (5-fluoro-2-methoxybenzamido) -2,2-dimethyl-7-methoxy-4-chromanol

Prepared in analogy to Example 15d using 23.9 g (64 mmol) of 3- (5-fluoro-2-methoxybenzamido) -2,2-dimethyl-7-methoxychromanone. Reduction with sodium borohydride gives 3- (5-fluoro-2-methoxybenzamido) -2,2-dimethyl-7-methoxy-4-chromanol as two diastereomers, m.p. 156-157 ° C.

c) 3- (5-fluoro-2-methoxybenzamido) -2,2-dimethyl-7-methoxy-4-chroman

Analogously to Example 15e, 18.8 g (50 mmol) of 3- (5-fluoro-2-methoxybenzamido) -2,2-dimethyl-7-methoxy-4-chromanol are reduced. After chromatography on a column of silica gel, eluting with a 95: 5 mixture of dichloromethane and ethyl acetate,

3- (5-fluoro-2-methoxybenzamido) -2,2-dimethyl-7-methoxy-4-chromate as an oil.

d) 3- (5-fluoro-2-methoxybenzamido) -2,2-dimethyl-7-methoxy-6-sulfamoylchroman

This material was prepared in analogy to Example 15f using 17.2 g (47.9 mmol) of 3- (5-fluoro-2-methoxybenzamido) -2,2-dimethyl-7-methoxy-4-chroman. The melting point of the product after recrystallization from ethanol is 159-160 ° C.

Example 20

3- (5-fluoro-2-methoxybenzamido) -2,2-dimethyl-6- (ethylamino) -7-methoxy-chroman

C '''^' OC ^H ,

This material was prepared in an analogous manner to that of Example 19 using 0.31 ml (3.5 mmol) of ethyl isothiocyanate instead of methyl isothiocyanate. Mp 211 ° C.

Example 21

3- (5-fluoro-2-methoxybenzamido) -2,2-dimethyl-6- (isopropylaminothiocarbonylaminosulfonyl) -7-methoxychroman

CH ₃ CH ₃

I

CH

This material was prepared in a manner analogous to Example 19, using 0.35 ml (3.5 mmol) of isopropyl isothiocyanate instead of methyl isothiocyanate. Melting point: 156-157 ° C.

Example 22

3- (3-ethyl-4-methyl-2-oxo-3-pyrrole-1-carboxamido) -6- (methylaminothio-carbonylaminosulfonyl) -7-methoxychroman

2.05 g (5 mmol) of 3- (3-ethyl-4-methyl-2-oxo-3-pyroline-1-carboxamido) -6-sulfamoyl-7-methoxychroman, 2.07 g (15 mmol) gently the ground potassium carbonate and 0.44 g (6 mmol) of methyl isothiocyanate are suspended or dissolved in 20 ml of dimethylsulfoxide and the reaction mixture is stirred for 1 hour at 80 ° C. After cooling, it is poured into ice water and the product precipitated by acidification with hydrochloric acid. . After aspiration and drying, the crude product is purified by chromatography on a silica gel column, eluting with dichloromethane: glacial acetic acid (19: 1).

Mp 205 ° C.

Preparation of the starting compound 3- (3-ethyl-4-methyl-2-oxo-3-pyroline-1-carboxamido) -6-sulfamoyl-7-methoxychroman

To a solution of 8.2 g (46 mmol) of 3-amino-7-methoxychroman in 60 mL of tetrahydrofuran was added 8.43 g (52 mmol) of N, N'-carbonyldiimidazole (exothermic reaction). After stirring at room temperature for 1 hour, the mixture was evaporated in vacuo. The residue is melted with 6.51 g (52 mmol) of 3-ethyl-4-methyl-3-pyrrolin-2-one at 160-170 ° C for 1.5 to 2 hours and then chromatographed on a silica gel column using as 3: 1 ethyl acetate / petroleum ether was used. The combined fractions were evaporated and the residue was recrystallized from methanol. 3- (3-Ethyl-4-methyl-2-oxo-3-pyrrole-1-carboxamido) -7-methoxychroman, m.p. 118-119 ° C, is obtained. This product is normally introduced into chilled sulfonic acid at room temperature. The mixture was stirred at -15 ° C and allowed to warm to room temperature. After the usual work-up, the sulfochloride is converted to the sulfonamide as described in Example 1. The melting point of 3- (3-ethyl-4-methyl-2-oxo-3-pyroline-1-carboxamido) -6-sulfamoyl-7-methoxychroman is 225- 227 ° C.

Example 23

3- (3-ethyl-4-methyl-2-oxo-3-pyrrole-1-carboxamido) -6- (methylarninocarbonyl aminosulfonyl) -7-methoxychroman

g 3- (3-ethyl-4-methyl-2-oxo-3-pyrrole-1-carboxamido) -6- (methylaminothiocarbonylaminosulfonyl) -7-methoxychroman (see Example 22) is suspended or dissolved in 20 ml 0.5 N-sodium hydroxide solution cooled to -5 ° C. At -5 to 0 ° C, 1 ml of 35% hydrogen peroxide solution is added and the reaction mixture is stirred for 1.5 hours at 0 ° C. 2 N hydrochloric acid and purified by silica gel column chromatography using a 9: 1 mixture of dichloromethane and glacial acetic acid as the eluent. Melting point: 245-246 ° C.

Pharmacological data

In the following models, the therapeutic properties of the compounds of formula I are demonstrated

Test 1

Duration of action potential on guinea pig papillary muscle (a) Introduction

ATP deficiency states observed during ischemia in cardiac muscle cells lead to a shortened duration of action potential. It is considered to be one of the main causes of so-called reentry arrhythmias, which can cause sudden cardiac death.

This is due to the opening of ATP-sensitive potassium channels due to a decrease in ATP levels.

(b) Method

A standard procedure using microelectrodes is used to measure the action potential. Here, the guinea pigs of both sexes are killed by a blow to the head, the hearts are removed, the papillary muscles are separated and hung into an organ bath. The organ bath was washed with Ringer's solution (0.9% sodium chloride, 0.048% potassium chloride, 0.024% calcium chloride, 0.02% sodium bicarbonate and 0.1% glucose) and

gassed the mixture 95 % oxygen and 5% oxide carbon dioxide at at 36 ° C. Muscle is irritated by electrode with rectangular pulses 1 V with duration 1 ms and frequency 2 Hz. Action potential is being investigated by intracellular injected glass

electrode, which is filled with 3 M potassium chloride solution and registered. The compounds to be tested are added to Ringer's solution at a concentration of 2 x 10 -5 moles / l or 2 x 10 -5 moles / l. The action potential is amplified by an amplifier and converted to an oscilloscope. The duration of the action (ms) is determined at step. Shortening of the action potential is induced by the addition of a HOE 234 potassium channel opener solution (Rilmakalim) (W. Linz, E. Klaus, U. Albus, R. H. A. Becker, D.

(Hugo Sachs) repolarization potential of milliseconds 95% (APD95).

Mania, H. C. Englert, B.

A.

Scholkens, Arzneimittelforschung

42 (11), 1180-1185 (1994)), wherein the concentration of HOE 234 in the bath solution is 1 µg / ml. Test substances are added to the bath solution as stock solutions in propanediol. Values given refer to measurements 30 minutes after addition. As a control, the APD95 value in the presence of HOE 234 s is used in the absence of test substance.

(c) Results

The following values were measured:

compound concentration APD95 - HOE 234 inspection <40 from of Example 1 20 pmol / l 157 ± 36 (158 ± 12) (n = 3) from of Example 3 20 | imol / l 134 ± 9 (178 ± 8) (n = 3) from of Example 6 2 μτηοΐ / ΐ 145 ± 19.1 (187 ± 10.2) (n = 3) from of Example 7 2 pmol / l 130 ± 28.1 (173 ± 13.1) (n = 3) from of Example 21 2 μτηοΐ / ΐ 67 ± 10 (149 ± 3) (n = 3)

For the measured values (average of n measurements) there are forgotten empty values in brackets. The empty values are the APD values measured at the start of the experiment without HOE 234 and the test substance in Ringer's solution. The values found suggest a normalizing effect of the compounds of the invention on shortening the duration of action potential.

Test 2

Membrane potential on isolated β-cells (a) Introduction

The mechanism of action of the sulfonylureas reducing the amount of sugar in the blood is well known. The target organs of these sulfonylureas are pancreatic β-cells, where these compounds release the hormone insulin, which reduces the amount of sugar in the blood, by influencing the electrical potential of the cell membrane. A hypoglycaemic sulfonylurea, such as glibenclamide, causes depolarization of the cell membrane, resulting in increased calcium ion influx and, as a result, insulin release. The degree of Δϋ of this cell membrane depolarization caused by the compounds of the invention is determined on the insulin secreting cells of the RINm5F pancreatic tumor cell line. From the action of the compound in this model, a measure of the effect of the compound on reducing blood sugar is predicted.

(b) Method

Cell culture of RINm5F cells:

RINm5F cells are cultured in RPMI 1640 (Flow) culture medium with the addition of 11 mmol glucose, 10% (v / v) fetal calf serum, 2 mmol glutamine and 50 µg / ml gentamycin at 37 ° C. The cells are seeded on petri dishes and stored in a humidified atmosphere containing 95% oxygen and 50% carbon dioxide at 37 ° C. For testing, cells are isolated by incubation in a calcium-free medium containing 0.25% trypsin for about 3 days. minutes.

Measurement method:

Isolated RINm5F cells are placed in a plexiglass vessel under an inverted microscope equipped with differential interference contrast optics. In a 400x magnification optical control, a flame-polished micropipette with an aperture diameter of approximately 1 µm is set per cell with a micromanipulator. By applying a slight vacuum inside the pipette, a high electrical seal is first obtained between the glass and the cell membrane. Then, by increasing the vacuum, part of the membrane under the measuring pipette is torn off. In this whole-cell arrangement, the cell potential is registered with a Patch-Clamp-Verstäker L / M EPC 7 (List, Darmstadt) and the whole-cell current is measured by applying a voltage ramp. The pipette is filled with a potassium chloride solution containing 140 mmol / l potassium chloride, 10 mmol / l sodium chloride, 1.1 mmol / l magnesium chloride, 0.5 mmol / l EGTA, 1 mmol / l Mg-ATP and 10 mmol / l HEPES (4-2 (hydroxyethyl) -1-piperazinethanesulfonic acid) and having a pH of 7.2. The bath contains a sodium chloride solution containing 140 mmol / l sodium chloride, 4.7 mmol / l potassium chloride, 1.1 mmol / l magnesium chloride, 2 mmol / l calcium chloride and 10 mmol / l HEPES, and whose pH is 7.4. Stock solutions of 100 mmol / l in dimethylsulfoxide (DMSO) and corresponding dilutions in sodium chloride solution are prepared from the test substances. Dimethyl sulfoxide alone has no effect on cell potential. Diazoxide (ATP-sensitive potassium channel opener) was added to the bath solution to stabilize the cell potential in all experiments at a concentration of 100 pmol / L. All experiments are performed at 34 ± 1 ° C.

(c) Results

The following AU values (changes in cell potential due to addition of test substances) were measured. Control values in parentheses are the cellular potentials of U prior to addition of test substances. By way of comparison, the values obtained in this test are glibenclamide, a typical hypoglycemic benzenesulfonylurea. The observed values indicate that the compounds of the invention show no, or little, hypoglycemic action.

compound concentration

AU (mV) of Example 1 of Example 1 of Example 3 of Example 3 of Example 6 of Example 7 glibenclamide glibenclamide

1 pmol / L 6 (Check: -74 mV) 10 pmol / L 24 (Check: -74 mV) 1 pmol / L 18 (Check: -69 mV) 10 pmol / L 23 (Check: -69 mV) 1 pmol / L 3 (Check: -76 mV) 1 pmol / L 29 (Check: -78 mV) 1 pmol / L 47 (Check: -73 mV) 10 pmol / L 46 (Check: -73 mV)

Claims (17)

PATENT CLAIMS 3-Amidochromanylsulfonyl (thio) ureas of general formula (I) (2) wherein: R ^{@ 1} represents a hydrogen atom, an alkyl group having 1, 2, 3 or 4 carbon atoms, an alkoxy group having 1, 2, 3 or 4 carbon atoms, an alkoxyalkoxy group containing independently of each alkoxy unit 1, 2, 3 or 4 carbon atoms; 1, 2, 3 or 4 carbon atoms, fluorine, chlorine, bromine or iodine or trifluoromethyl, R ^2a , R ^2b and R ^2c , which are the same or different, each represent a hydrogen atom or an alkyl group having 1 or 2 atoms alkyl, R ³ represents a hydrogen atom or an alkyl group having 1, 2, 3 or 4 carbon atoms Z represents a sulfur or oxygen atom, and A represents a phenyl group which is unsubstituted or substituted by up to three identical or different substituents selected from the group consisting of halogen atoms, alkyl groups having 1 or 2 carbon atoms and alkoxy groups having 1 or 2 carbon atoms, or A represents the remainder of a saturated or unsaturated lactam of formula "__" B About where B represents an alkenylene or alkylene group having 3, 4, 5 or 6 carbon atoms which is unsubstituted or substituted by up to three identical or different alkyl groups having 1, 2, 3 or 4 carbon atoms, or A represents the rest of the bicyclic system of one of the formulas in all their stereoisomeric forms and mixtures thereof in all ratios, as well as their physiologically acceptable salts. 2. 3-Amidochromanylsulfonyl (thio) ureas of general formula I according to claim 1, wherein R ^{@ 1} is hydrogen, alkyl having 1 or 2 carbon atoms, alkoxy having 1, 2, 3 or 4 carbon atoms, alkylthio having 1, 2, 3 or 4 carbon atoms, fluorine, chlorine, bromine or iodine or trifluoromethyl R ^2a , R ^2b and R ^2c , which are the same or different, each represent a hydrogen atom or an alkyl group having 1 or 2 carbon atoms, R ³ represents a hydrogen atom or an alkyl group having 1, 2, 3 or 4 carbon atoms Z represents a sulfur or oxygen atom, and A represents a phenyl group which is unsubstituted or substituted by up to three identical or different substituents selected from the group consisting of halogen atoms, alkyl groups having 1 or 2 carbon atoms and alkoxy groups having 1 or 2 carbon atoms, or A represents the remainder of a saturated or unsaturated lactam of formula where B represents an alkenylene or alkylene group having 3, 4, 5 or 6 carbon atoms which is unsubstituted or substituted by up to three identical or different alkyl groups having 1, 2, 3 or 4 carbon atoms, or A represents the rest of the bicyclic system of one of the formulas in all their stereoisomeric forms and mixtures thereof in all ratios, as well as their physiologically acceptable salts. 3. 3-Amidochromanylsulfonyl (thio) ureas of general formula I according to claim 1 and / or 2, in which R ¹ is H, alkyl having 1 or 2 carbon atoms, alkoxy having 1 or 2 carbon atoms, alkylmercapto having 1 or 2 carbon atoms, F, Cl, Br, I or trifluoromethyl; R ^2a represents a hydrogen atom R ^2b and R ^2c each represent a hydrogen atom or a methyl group, R ³ represents a hydrogen atom or an alkyl group having 1, 2, 3 or 4 carbon atoms Z represents a sulfur or oxygen atom, and A represents a phenyl group which is unsubstituted or substituted by up to three identical or different substituents selected from the group consisting of halogen atoms, alkyl groups having 1 or 2 carbon atoms and alkoxy groups having 1 or 2 carbon atoms, or A represents the remainder of a saturated or unsaturated lactam of formula where B represents an alkenylene or alkylene group having 3, 4, 5 or 6 carbon atoms which is unsubstituted or substituted by up to three identical or different alkyl groups having 1, 2, 3 or 4 carbon atoms, or A represents the rest of the bicyclic system of one of the formulas in all their stereoisomeric forms and mixtures thereof in all ratios, as well as their physiologically acceptable salts 4. 3-Amidochromanylsulfonyltiomočoviny formula I according to one or more of Claims 1 to 3, wherein R ¹ is H, alkyl having 1 or 2 carbon atoms, alkoxy having 1 or 2 carbon atoms or alkylmercapto having 1 or 2 carbon atoms , R ^2a , R ^2b and R ^2c are each hydrogen, R ³ represents a hydrogen atom or an alkyl group having 1, 2, 3 or 4 carbon atoms Z represents a sulfur atom, and A represents a phenyl group which is unsubstituted or substituted by up to three identical or different substituents selected from the group consisting of halogen atoms, alkyl groups having 1 or 2 carbon atoms and alkoxy groups having 1 or 2 carbon atoms, or A represents the remainder of a saturated or unsaturated lactam of formula ABOUT B represents an alkenylene or alkylene group having 3, 4, 5 or 6 carbon atoms which is unsubstituted or substituted by up to three identical or different alkyl groups having 1, 2, 3 or 4 carbon atoms, or A represents the rest of the bicyclic system of one of the formulas in all their stereoisomeric forms and mixtures thereof in all ratios, as well as their physiologically acceptable salts 5. 3-Amidochromanylsulfonyltiomočoviny of the formula I according to one or more of claims 1 to 4, wherein R ¹ is H, alkyl having 1 or 2 carbon atoms, alkoxy having 1 or 2 carbon atoms or alkylmercapto having 1 or 2 carbon atoms R ^2a , R ^2b and R ^2c are each hydrogen, R ³ represents a hydrogen atom, a methyl group and an ethyl group Z represents a sulfur atom, and A represents a phenyl group which is unsubstituted or substituted by up to three identical or different substituents selected from the group consisting of halogen atoms, alkyl groups having 1 or 2 carbon atoms and alkoxy groups having 1 or 2 carbon atoms, or A represents the remainder of a saturated or unsaturated lactam of formula where B represents an alkenylene or alkylene group having 3, 4, 5 or 6 carbon atoms which is unsubstituted or substituted by up to three identical or different alkyl groups having 1, 2, 3 or 4 carbon atoms, in all their stereoisomeric forms and mixtures thereof in all ratios as well as their physiologically acceptable salts. The 3-amidochromanylsulfonylthiourea of formula I according to one or more of claims 1 to 5, wherein: R ¹ is H, alkyl having 1 or 2 carbon atoms, alkoxy having 1 or 2 carbon atoms or alkylmercapto having 1 or 2 carbon atoms; R ^2a, R ^2b and R ^2c are hydrogen. R ³ represents a hydrogen atom, a methyl or ethyl group Z represents a sulfur atom, and A represents a phenyl group which is unsubstituted or substituted by up to three identical or different substituents selected from the group consisting of halogen atoms, alkyl groups of 1 or 2 carbon atoms and alkoxy groups of 1 or 2 carbon atoms, in all their stereoisomeric forms and mixtures thereof in all ratios as well as their physiologically acceptable salts. 3-Amidochromanylsulfonylureas of the formula I according to one or more of claims 1 to 3, in which: R ¹ is H, alkyl having 1 or 2 carbon atoms, alkoxy having 1 or 2 carbon atoms or alkylmercapto having 1 or 2 carbon atoms; R ^2a, R ^2b and R ^2c are hydrogen. R ³ is H or alkyl having 1, 2, 3 or 4 carbon atoms, Z represents an oxygen atom, and A represents a phenyl group which is unsubstituted or substituted by up to three identical or different substituents selected from the group consisting of halogen atoms, alkyl groups having 1 or 2 carbon atoms and alkoxy groups having 1 or 2 carbon atoms. or A represents a residue of a saturated or unsaturated lactam of the general formula wherein B represents an alkenylene or alkylene group having 3, 4, 5 or 6 carbon atoms which is unsubstituted or substituted by up to three identical or different alkyl groups having 1, 2, 3 or 4 carbon atoms, or A represents the rest of the bicyclic system of one of the formulas in all their stereoisomeric forms and mixtures thereof in all ratios, as well as their physiologically acceptable salts. A compound of formula I as claimed in one or more of claims 1, 2, 3 and 7, wherein R ¹ represents a hydrogen atom, an alkyl group having 1 or 2 carbon atoms, an alkoxy group having 1 or 2 carbon atoms or an alkylthio group having 1. or 2 carbon atoms, R ^2a , R ^2b and R ^2c are each hydrogen, R ³ represents a hydrogen atom, a methyl or ethyl group; Z represents an oxygen atom, and A represents a phenyl group which is unsubstituted or A substituted with up to three identical or different substituents selected from the group consisting of halogen atoms, alkyl groups and 1 or 2 carbon atoms and alkoxy groups having 1 or 2 carbon atoms. or A represents a residue of a saturated or unsaturated lactam of the general formula wherein B is alkenylene or alkylene having 3, 4, 5 or 6 carbon atoms, which is unsubstituted or substituted by up to three identical or different alkyl having 1, 2, 3 or 4 C _e alkyl, in all their stereoisomeric forms and mixtures thereof in all ratios, as well as their physiologically acceptable salts. The 3-amidochromanylsulfonylureas of formula I according to one or more of claims 1, 2, 3, 7 and 8, wherein: R ¹ represents a hydrogen atom, an alkyl group having 1 or 2 carbon atoms, an alkoxy group having 1 or 2 carbon atoms, or The thi alkylthio group having 1 or 2 carbon atoms, R ^2a , R ^2b and R ^2c are each hydrogen, R ³ represents a hydrogen atom, a methyl or ethyl group Z represents an oxygen atom, and A represents a phenyl group which is unsubstituted or substituted by up to three identical or different substituents selected from the group consisting of halogen atoms, alkyl groups of 1 or 2 carbon atoms and alkoxy groups of 1 or 2 carbon atoms, in all their stereoisomeric forms and mixtures thereof in all ratios as well as their physiologically acceptable salts. Process for the preparation of 3-amidochromanylsulfonyl (thio) ureas of the formula I according to one or more of claims 1 to 9, characterized in that the chromanylsulfonamides of the formula III H. (III) or a salt of formula (IV) thereof M (IV) R in which the individual symbols have the meanings defined in claims 1 to 9 and the cation M represents an alkali metal or alkaline earth metal ion or an ammonium ion, is reacted with R 3 -substituted isocyanate or R 3 -substituted isothiocyanate with R ³ -substituted carbonic acid derivative or, for the preparation of 3-amidochromanylsulfonylureas of the formula I in which Z represents an oxygen atom, with ³ -substituted-trichloroacetamide on the nitrogen R, or R ³ is hydrogen, compounds of formula III or IV are reacted with trialkylsilylizo (thio) cyanate or with silicontetraizo (thio) cyanate and primarily silicon-substituted chromanylsulfonyl (thio) ureas cleaved, or by the formation of 3-amidochromanylsulfonylureas to prepare 3-amidochromanylsulfonylureas in which Z represents an oxygen atom, z1 substituting Compound of formula VIII, C ABOUT II (VIII), wherein the individual symbols have the meanings defined in claims 1 to 9, react with R ³ -substituted urea * or R ³ -substituted bis (trilakylsilyl) urea, or that compounds of formula IX or X o = c = N— (ix) Wherein each of the individual symbols is as defined in claims 1 to 9, is reacted with an amine of the formula R ³ -NH 2, wherein R is as defined in claims 1 to 9, or that to prepare the 3-amidochromanylsulfonylureas of formula I, in which Z represents an oxygen atom, desulphurizes the 3-amidochromanylsulfonylthioureas of formula I in which Z represents a sulfur atom. The 3-amidochromanylsulfonyl (thio) urea of formula I according to one or more of claims 1 to 9 and / or its physiologically acceptable salts for use as a medicament. Use of 3-amidochromanylsulfonyl (thio) ureas of the formula I according to one or more of Claims 1 to 9 and / or their physiologically acceptable salts for the preparation of a medicament for the treatment or prophylaxis of cardiovascular disorders, cerebral vascular diseases, ischemic heart conditions. cardiac output or to improve cardiac function after heart transplants. Use of the 3-amidochromanylsulfonyl (thio) ureas of the formula I according to one or more of claims 1 to 9 and / or their physiologically acceptable salts for the preparation of a medicament for the treatment or prophylaxis of cardiac rhythm disorders or prevention of sudden cardiac death. The 3-amidochromanylsulfonyl (thio) ureas of formula I according to one or more of claims 1 to 9 and / or their physiologically acceptable salts for use in the treatment or prophylaxis of disorders of the cardiovascular system, cerebral vascular diseases, ischemic heart conditions, attenuated cardiac output, or to improve cardiac function after heart transplants. The 3-amidochromanylsulfonyl (thio) urea of formula (I) according to one or more of claims 1 to 9 and / or their physiologically acceptable salts for use in the treatment or prophylaxis of cardiac rhythm disorders or to prevent sudden cardiac death. Use of 3-amidochromanylsulfonyl (thio) ureas of the formula I according to one or more of claims 1 to 9 and / or their physiologically acceptable salts for inhibiting ATP-sensitive potassium channels. Pharmaceutical preparation, characterized in that it contains, in addition to pharmaceutically acceptable carriers and / or excipients, an effective amount of at least one 3-amidochromanylsulfonyl (thio) urea of the formula I according to one or more of claims 1 to 9 and / or their physiologically an acceptable salt.